Spinal cord injury (SCI) treatment represents a critical issue in clinical research and patient care. Stem cell-based replacement therapies have already been proposed worldwide, especially studying stem cells from the adult bone marrow stroma. Previous studies focusing on those cells did not specifically consider their intrinsic embryonic heterogeneity, thus intermingling different stem cells subpopulations to treat experimental SCI or even injured patients. In this study, we decided to compare adult bone marrow neural crest-derived stem cells (NCSC) and mesenchymal stem cells (MSC), and highlight which of their specific properties could be relevant in therapeutic perspectives. In that purpose, we compared NCSC and MSC isolated from adult mouse bone marrow. We then compared the effects that both cell types could exert once grafted inside an injured spinal cord. Cells were injected into the spinal cord of mice that right after a spinal cord contusion at the T11-12 spinal level. Our results indicate that both MSC and NCSC-injected mice recovered locomotion abilities faster than control mice (as assessed by BMS scoring). Additionally, we observed that after 28 days post-injury, the lesion volume tended to decrease in mice that received cell graft compared to control group. Interestingly, it appeared that MSC seemed to be able to modulate inflammation inside the lesion, more than NCSC. Indeed, MSC-graft increased early neutrophil and macrophage recruitment in the bloodstream and inside the spinal cord, and increased the number of arginase-1-expressing cells remaining in the spinal cord after 28 days. In parallel, we compared the secretome of both NCSC and MSC, and noticed some interesting differences: MSC secreted several chemokines reflecting possible immunomodulating properties, while NCSC secreted products might be able to enhance neurite outgrowth. Indeed, preliminary data showed that NCSC induced neuritogenesis on primary neurons in vitro. Altogether, those results should help to improve and optimize cell-based therapies parameters and/or to define precise and efficient pharmacological treatments for SCI patients. [less ▲]

Objectives: Spinal cord injury (SCI) treatment represents a critical issue in clinical research and patient care. Stem cell-based replacement therapies have already been proposed worldwide, especially studying stem cells from the adult bone marrow stroma. Previous studies focusing on those cells did not specifically consider their intrinsic embryonic heterogeneity, thus intermingling different stem cells subpopulations to treat experimental SCI or even injured patients. In this study, we decided to compare adult bone marrow neural crest-derived stem cells (NCSC) and mesenchymal stem cells (MSC), and highlight which of their specific properties could be relevant in therapeutic perspectives. Material and methods: In that purpose, we compared NCSC and MSC isolated from adult mouse bone marrow. We then compared the effects that both cell types could exert once grafted inside an injured spinal cord. Cells were injected into the spinal cord of mice that right after a spinal cord contusion at the T11-12 spinal level. Results: Both MSC and NCSC-injected mice recovered locomotion abilities faster than control mice (as assessed by BMS scoring). Additionally, we observed that after 28 days post-injury, the lesion volume tended to decrease in mice that received cell graft compared to control group. Interestingly, it appeared that MSC seemed to be able to modulate inflammation inside the lesion, more than NCSC. Indeed, MSC-graft increased early neutrophil and macrophage recruitment in the bloodstream and inside the spinal cord, and increased the number of arginase-1-expressing cells remaining in the spinal cord after 28 days. In parallel, we compared the secretome of both NCSC and MSC, and noticed some interesting differences: MSC secreted several chemokines reflecting possible immunomodulating properties, while NCSC secreted products might be able to enhance neurite outgrowth. Conclusions: Preliminary data showed that NCSC induced neuritogenesis on primary neurons in vitro. Altogether, those results should help to improve and optimize cell-based therapies parameters and/or to define precise and efficient pharmacological treatments for SCI patients. [less ▲]

Spinal cord injuries remain a critical issue in experimental and clinical research nowadays, and it is now well accepted that the immune response and subsequent inflammatory reactions are of significant ... [more ▼]

Spinal cord injuries remain a critical issue in experimental and clinical research nowadays, and it is now well accepted that the immune response and subsequent inflammatory reactions are of significant importance in regulating the damage/repair balance after injury. The role of macrophages in such nervous system lesions now becomes clearer and their contribution in the wound healing process has been largely described in the last few years. Conversely, the contribution of neutrophils has traditionally been considered as detrimental and unfavorable to proper tissue regeneration, even if there are very few studies available on their precise impact in spinal cord lesions. Indeed, recent data show that neutrophils are required for promoting functional recovery after spinal cord trauma. In this review, we gathered recent evidence concerning the role of neutrophils in spinal cord injuries but also in some other neurological diseases, highlighting the need for further understanding the different mechanisms involved in spinal cord injury and repair. [less ▲]

Spinal cord injured experimental animals are widely used for studying pathophysiological processes after central nervous system acute traumatic lesion and elaborating therapeutic solutions, some of them ... [more ▼]

Spinal cord injured experimental animals are widely used for studying pathophysiological processes after central nervous system acute traumatic lesion and elaborating therapeutic solutions, some of them based on stem cell transplantation. Here, we describe a protocol of spinal cord contusion in C57BL/6J mice, directly followed by bone marrow stromal stem cells transplantation. This model allows for the characterization of neuroprotective and neurorestorative abilities of these stem cells in a context of spinal cord trauma. [less ▲]

Since several years, adult/perinatal mesenchymal and neural crest stem cells have been widely used to help experimental animal to recover from spinal cord injury. More interestingly, recent clinical ... [more ▼]

Since several years, adult/perinatal mesenchymal and neural crest stem cells have been widely used to help experimental animal to recover from spinal cord injury. More interestingly, recent clinical trials confirmed the beneficial effect of those stem cells, which improve functional score of patients suffering from such lesions. However, a complete understanding of the mechanisms of stem cell-induced recovery is seriously lacking. Indeed, spinal cord injuries gathered a wide range of biochemical and physiopathological events (such as inflammation, oxidative stress, axonal damage, demyelination, etc) and the genuine healing process after cell transplantation is not sufficiently defined. This review aims to sum up recent data about cell therapy in spinal cord lesions using mesenchymal or recently identified neural crest stem cells, by describing precisely which physiopathological parameter is affected and the exact processes underlying the observed changes. Overall, although significant advances are acknowledged, it seems that further deep mechanistic investigation is needed for the development of optimized and efficient cell-based therapy protocols. [less ▲]

Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage ... [more ▼]

Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage differentiation abilities, then constituting an attractive and easy-available source of material for cell therapy in neurological disorders. Whereas the in vivo integration and differentiation of BMSC in neurons into the central nervous system is currently matter of debate, we report here that once injected into the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, pure populations of either bone marrow neural crest stem cells (NCSC) or mesenchymal stem cells (MSC) survived only transiently into the lesioned brain. Moreover, they do not migrate through the brain tissue, neither modify their initial phenotype, while no recovery of the dopaminergic system integrity was observed. Consequently, we tend to conclude that MSC/NCSC are not able to replace lost neurons in acute MPTP-lesioned dopaminergic system through a suitable integration and/or differentiation process. Altogether with recent data, it appears that neuroprotective, neurotrophic and anti-inflammatory features characterizing BMSC are of greater interest as regards CNS lesions management. [less ▲]

Adult stem cells are endowed with in vitro multi-lineage differentiation abilities, and constitute an attractive autologous source of material for cell therapy in neurological disorders. With regards to ... [more ▼]

Adult stem cells are endowed with in vitro multi-lineage differentiation abilities, and constitute an attractive autologous source of material for cell therapy in neurological disorders. With regards to lately published results, the ability of adult mesenchymal stem cells (MSC) and neural crest stem cells (NCSC) to integrate and differentiate into neurons once inside the central nervous system (CNS) is currently questioned. In this review, we collected exhaustive data on MSC/NCSC neural differentiation in vitro. We then analyzed pre-clinical cell therapy experiments in different models for neurological diseases and concluded that neural differentiation is probably not the leading property of adult MSC and NCSC concerning neurological pathologies management. Definitely, a fine analysis of the molecules that are secreted by MSC and NCSC would be of significant interest regarding their important contribution to the clinical and pathological recovery after CNS lesions. [less ▲]

Bone marrow stromal cells are adult multipotent cells that represent an attractive tool in cellular therapy strategies. Several studies have reported that in vitro passaging of mesenchymal stem cells alters the functional and biological properties of those cells, leading to the accumulation of genetic aberrations. Recent studies described bone marrow stromal cells (BMSC) as mixed populations of cells including mesenchymal (MSC) and neural crest stem cells (NCSC). Here, we report the transformation of NCSC into tumorigenic cells, after in vitro long-term passaging. Indeed, the characterization of 6 neural crest-derived clones revealed the presence of one tumorigenic clone. Transcriptomic analyses of this clone highlighted, among others, numerous cell cycle checkpoint modifications and chromosome 11q down-regulation (suggesting a deletion of chromosome 11q) compared with the other clones. Moreover, unsupervised analysis such as a dendrogram generated after agglomerative hierarchical clustering comparing several transcriptomic data showed important similarities between the tumorigenic neural crest-derived clone and mammary tumor cell lines. Altogether, it appeared that NCSC isolated from adult bone marrow represents a potential danger for cellular therapy, and consequently, we recommend that phenotypic, functional and genetic assays should be performed on bone marrow mesenchymal and neural crest stem cells before in vivo use, to demonstrate whether their biological properties, after ex vivo expansion, remain suitable for clinical application. [less ▲]

The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The ... [more ▼]

The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crest stem cells (NCSC) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSC), including their similarities and differences. In this paper, using transcriptomic as well as proteomic technologies, we compared NCSC to MSC and stromal nestin-positive cells, all of them isolated from adult bone marrow. We demonstrated that the nestin-positive cell population, which was the first to be described as able to differentiate into functional neurons, was a mixed population of NCSC and MSC. More interestingly, we demonstrated that MSC shared with NCSC the same ability to truly differentiate into Tuj1-positive cells when co-cultivated with paraformaldehyde-fixed cerebellar granule neurons. Altogether, those results suggest that both NCSC and MSC can be considered as important tools for cellular therapies in order to replace neurons in various neurological diseases. [less ▲]

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in industrialized countries. Its main characteristic relies in a progressive loss of dopaminergic (DA) neurons in the ... [more ▼]

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in industrialized countries. Its main characteristic relies in a progressive loss of dopaminergic (DA) neurons in the Substantia Nigra pars compacta (SNpc), resulting in a deficient dopamine release in the striatum and then promoting important defects in motility regulation. Unfortunately, motor symptoms are generally diagnosed once 80% of nigrostriatal neurons are already lost. The emergence of neuroprotective/-restorative strategies is then increasingly raising hope, and a lot of people now focus on cell therapy experiments. Adult bone marrow stromal stem cells (BMSCs) have already been demonstrated as ideal candidates for cell therapy in nervous lesions, regarding their high multipotency and the fact they can be easily harvested in the patient himself. After it has been demonstrated that some BMSCs arise from the embryonic neural crest (NC), we compared NC-BMSCs and mesenchymal (M)-BMSCs in vitro, in terms of differenciation abilities and more particularly in terms of neural fate. We then wanted to investigate and compare the potential usefulness of both populations in the context of a neurological pathology. We have validated a MPTP mouse model, mimicking the specific loss of nigral neurons, and started setting up a cell therapy experiment using stereotaxic brain injection of the two types of BMSCs. The survival rate of grafted cells was analyzed as well as their migration or differentiation, and their ability to restore neuronal loss was also observed. Our first results showed that once grafted inside the brain of MPTP mice, NC-BMSCs survive for about a week, staying tightly close to each other the injection track with no visible sign of migration. Afterwards, cells begin to disappear and we only observe a mean survival rate of 1% after 28 days. Looking at the nigrostriatal pathway integrity, neural crest-BMSCs don’t seem to induce any improvement: they don’t differenciate into neural cells, neither replace lost DA cells, and they do not induce any sprouting of surviving DA neurons. While the M-BMSCs graft experiment has to be completed, these first results showed that NC-BMSCs at the stem cell state are not able to restore the lesioned system, and maybe a pre-differenciation step would be required to trigger those cells into a neuronal fate before grafting them in a MPTP-mouse brain. [less ▲]